1. Field of the Invention
The present invention relates to new molecules, designated LDCAM, capable of modulating or altering T cell function. More particularly, the present invention involves novel polypeptides that interact with T cell surface molecules to alter signaling, bind to themselves and bind to another novel polypeptide, designated B7L-1, and generate increases in natural killer cell populations. The invention includes LDCAM molecules, DNA encoding LDCAM molecules, processes for production of recombinant LDCAM polypeptides, and pharmaceutical compositions containing such LDCAM polypeptides.
2. Description of Related Art
Adhesion molecules play important roles in cell signaling within the immune system and other cellular systems. In addition to the antigen specific signals delivered by the T cell receptor complex, the shape and type of immune response by T cells depend upon costimulatory signals mediated by adhesion molecules on antigen presenting cells (APC). One such costimulatory signaling involves the adhesion molecules B7-1 (CD80) and B7-2 (CD86) which send important signals through their T cell surface receptors, CD28 and CTLA4 (CD152). B7-1 interacts with CD28 to signal cytokine production, cell proliferation, and the generation of effector and memory T cells. If the signal through CD28 is blocked, T cell anergy or immune deviation can occur, resulting in severely depressed or altered immune responses.
B7-1 also interacts with the T cell CTLA4 receptor. Its signaling is complex, but one component provides a negative feedback signal, causing the T cell to attenuate the CD28 signal. In the absence of this signal, rampant T cell proliferation and effector cell activation continues. When this feedback regulation malfunctions, autoimmune diseases and lymphoproliferation can result. For example, when the CD28 and B7-1 (and B7-2) interaction is blocked with an anti-CTLA4 antibody, increased tumor immunity and lymphoproliferation have been observed.
B7-2, which is expressed on different cells and at different stages of APC activation from that of B7-1, also delivers its costimulatory signal to T cells through CD28 and CTLA4. The B7-2 signal can lead to immune responses that are identical to, or different from the immune responses resulting from B7-1 signaling. The nature of the B7-2 signaling depends upon the cellular context and the timing of the costimulation.
Even though they bind to the same cellular receptors, B7-1 and B7-2 are only weakly related at the amino acid level. Both, however, are members of the extended immunoglobulin domain containing superfamily and much of their shared sequence homology is due to the particular residues shared by their common Ig domains, which are characteristic of the Ig-domain subfamily.
There is evidence to suggest that other adhesion molecules are important in T cell response to antigens. For example, T cell proliferation and cytokine production that occurs in response to engagement of a T cell receptor by an antigen can occur in the absence of CD28 in certain diseases. Proliferation and cytokine production also occurs in the absence of CD28 in memory responses, and in systems in which CD28 has been genetically removed. In some cases, T cell proliferation depends upon an interaction within the CD48 or the ICAM/LFA systems. Furthermore, the adhesion molecule known as ALCAM interacts with its T cell ligand CD6 to modulate the CD3 signal.
Clearly, signaling through T cell surface receptors plays an important role in maintaining balance in the immune system. Systems with a predominance of activatory signals, such as the costimulatory signaling between CD28 and B7-1, can lead to autoimmunity and inflammation. Immune systems with a predominance of inhibitory signals, such as the costimulatory signaling between CTLA4 and are less able to challenge infected cells or cancer cells. Isolating new molecules involved in T cell signaling is highly desirable for studying the biological signal(s) transduced via their receptors. Additionally, identifying such molecules provides a means of regulating and treating diseased states associated with autoimmunity, inflammation and infection.